Highly pathogenic avian influenza (HPAI) viruses are likely to cause an influenza pandemic at some point in the future. Traditional methods of influenza vaccine production will probably be too slow to allow an effective response to such a pandemic. Development of rapidly deployable vaccine platforms capable of protecting against such a pandemic is therefore of major importance. Vaccine vectors based on recombinant live, attenuated or replication- defective vesicular stomatitis virus (VSV) are among the most potent vaccine vectors tested to date. They also have a major advantage in that there is no pre-existing immunity to the vector in the human population. VSV vectors expressing an H5N1 hemmaglutinin (HA) protein from an HPAI virus induce high-titer broadly neutralizing (cross-clade) antibodies in both mice and non-human primates. They also protect against lethal AIV infection. The goal of the current project is to further develop and test novel, optimized, VSV-based AIV vaccine vectors that produce much higher levels of the AIV HA. These vectors should also induce much higher neutralizing antibody titers and are expected to generate maximal cross-clade neutralizing antibody titers to AIVs. The optimized, highly attenuated or replication-defective, single-cycle VSV vectors to be developed could form the basis for a broadly protective AIV vaccine that could be produced and deployed rapidly in response to an influenza virus pandemic. PUBLIC HEALTH RELEVANCE: Influenza pandemics in the 20th century are estimated to have killed more than 40 million people worldwide. Future pandemics will surely occur and are highly likely to result from mutation of avian influenza virus and crossover into the human population. The goal of this project is to develop a novel type of vaccine that elicits very broad neutralizing antibody and broad protection against avian influenza virus strains. In addition, unlike traditional influenza vaccines, this vaccine could be produced and deployed rapidly to halt a pandemic.